This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT The availability of agents from new and existing ARV classes will improve the ability to achieve virologic suppression in triple class-experienced patients. The Department of Health and Human Services (DHHS) treatment guidelines recommend using at least two agents that are likely to be active in heavily treatment-experienced patients because HIV drug resistance will develop quickly if only one active agent is added to a failing regimen. Using another active agent such as ENF with TPV or DRV significantly increased the rate of virologic success (2.0 can be constructed. Achieving virologic suppression remains the goal for all patients starting or changing therapy. The availability of multiple new agents with activity against resistant virus may actually change the treatment paradigm for heavily ARV-experienced patients from one that emphasizes maintenance of immunologic function to one that expects a high likelihood of achieving suppression of plasma HIV-1 RNA to 2.0 versus not adding NRTIs, in subjects with triple-class ARV experience and expected multiple drug cross resistance. Because safety and pharmacokinetic data are not available from patients younger than 16 years for investigational agents, the study will enroll subjects of at least 16 years of age. In a highly treatment-experienced subject, a two-drug regimen is not likely to result in sustained viral suppression with the possible exception of drugs from two new classes such as integrase inhibitor plus ENF or integrase inhibitor plus MVC. In clinical trials, the activity of a DRV- or TPV-containing regimen was increased if ENF was also used as a na[unreadable]ve drug, presumably because ENF added a completely active agent (a cPSS of 1.0). Data on the activity or cPSS of either PI in these trials are not available but presumably the activity of the regimen with ENF was less than a cPSS of 2.0. The rates of viral suppression in these trials still did not exceed about 60%. In the BENCHMRK trials, at week 16, higher rates of virologic suppression (90% or more) were seen if one or two new agents were used in addition to RAL. Longer follow-up is needed to confirm the durability of this high degree of viral suppression in a highly treatment-experienced population. A5241 will enroll a patient population similar to the RESIST, POWER, BENCHMRK, MOTIVATE, and TORO studies with the goal of high rates (i.e., 75%) of virologic success at 48 weeks. This goal is unlikely to be achieved with a regimen that has a cPSS of 2.0 (2 active agents, or 1 active and 2 partially active agents averaging 0.5 each, or three partially active agents averaging 0.666 each). Nonetheless, how much activity is needed for a completely suppressive regimen is not known. A cPSS of 2.0 (and not just =2.0) will require higher activity of the entire regimen and precludes a two-drug regimen. In fact, study subjects will likely take regimens with cPSS from 2.1 to 3.0;therefore, the association of cPSS (over a range of values) to treatment response will be explored. In addition, the study will test the hypothesis that excluding NRTIs will not be an inferior approach in the setting of an active novel regimen. Subjects randomized to exclude NRTIs from a novel regimen that is expected to have a substantial virologic response would be more likely to achieve this goal. Randomization and analysis will be stratified by NRTI susceptibility with 2 levels for this stratification factor: susceptible to none of the NRTIs versus susceptible to one or more NRTIs. Susceptibility will be defined using information from the phenotype sensitivity assay report.